Carbanilate dithiolanes and dithianes

ABSTRACT

Substituted carbanilate dithiolanes and dithiane compounds having the formula   IN WHICH R is lower alkyl; R1, R2, R3, R4, R5, R6 and R7 each are independently selected from the group consisting of hydrogen and lower alkyl; X is selected from the group consisting of oxygen and sulfur; and n is 0 or 1. These compounds are useful as herbicides.

United States Patent 11 1 Teach CARBANILATE DITHIOLANES AND DITHIANES [75] Inventor: Eugene G. Teach, El Cerrito, Calif.

[73] Assignee: Stauffer Chemical Company, New

York, NY.

22 Filed: Oct. 26, 1971 21 Appl. No.: 192,317

[52] US. Cl. 260/327 M, 71/90 [51] Int. Cl. C07d 71/00, C07d 73/00 [58] Field of Search 260/327 M, 455 A,

[56] References Cited UNITED STATES PATENTS 3,461,137 8/1969 Weil et al; 260/327 Primary Examiner-Henry R. Jiles Assistant ExaminerCecilia M. S. Jaisle 1111 3,759,951 1451 Sept. 18, 1973 Attorney-Daniel C. Block et al.

[57] ABSTRACT Substituted carbanilate dithiolanes and dithiane compounds having the formula 13 Claims, N0 Drawings 2-PHENOXYALKANOIC ACID ESTERS This application is a division of application Scr. No. 737,837 filed June 18, i969.

The present invention relates to 2-phenoxyalkanoic acid esters. In particular, this invention concerns 2- phenoxyalkanoic acid alkoxyalkyl esters, 2- phenoxyalkanoic acid succinimido esters and 2- phenoxyalkanoic acid phthalimido esters which in standard and accepted pharmacological tests have demonstrated biological activity as serum cholesterol lowering agents.

The new and novel compounds within the scope of the present invention are exemplified by the following structural formula:

ivlit'arlsihli 'sselec'tariarfii group consisting of hydrogen, halogen, lower alkyl and lower alkoxy; R and R are selected from the group consisting of hydrogen and lower alkyl; and R is selected from the group consisting of lower alkoxy(lower)alkyl, succinimido and phthalimido. As employed herein the tenns lower alkyl, flower alkoxy and the like are meant to include both branched and straight chain moieties containing from one to eight carbon atoms. Typical examples of the compounds of this invention are: 2-(pchlorophenoxy)-2-methylpropionic acid, methoxy methyl ester; 2-(p-chlorophenoxy )-2-methylpropionic acid, succinimido ester; 2-(p-bromo'phenoxy)-'2- methylpropionic acid, succinimido ester; and 2-(pchlorophenoxy)-2-rnethylpropionic acid, phthalimido ester.

The new and novel 2-phenoxyalkanoic acid, alkoxyalkyl esters of the present invention may be prepared by the process which is hereinafter schematically illustrated:

(1) lul) wherein R}, R5, and R, aredefined as above and X is halogen and R, is lower alkoxy(lower)alkyl. The reaction is effected by admixing an appropriate 2- phenoxyalkanoic acid (X) with a haloalkyl alkylether (II), in the presence of a basic catalyst e.g. triethylamine, in ethyl acetate at about room temperature for a period of about one to about hours.

When the reaction is complete, the resulting 2- phenoxyalkanoic acid alkoxyalkyl ester (Ill) is separated by conventional procedures. For example, the reaction mixture is filtered, washed with water and concentrated.

The new and novel succinimido and phthalimido esters of these Z-phenoxyalkanoic acids may be prepared by the process which is depicted as follows:

wherein R,, R and R are defined as above andR is succinimido or phthalimido. The reaction is effected by admixing an appropriate 2-phenoxyalkanoic acid (I) with a basic catalyst e.g. triethylamine, in a reactioninert organic solvent at a temperature below about 0C. An alkylhalocarbonate e.g. ethylchloroforrnate is then added to this mixture, the temperature is allowed to equilibrate to about room temperature and the mixture is diluted with ethyl ether. Thereafter, a N-hydroxy succinimide or phthalimide (IV) is added to the reaction mixture with stirring.

When the reaction is complete, the resulting 2- phenoxyalkanoic acid succinimido or phthalimido ester (V) is separated by conventional procedures. For example, the reaction mixture is extracted with an aqueous bicarbonate solution, water and then concentrated to afford the product (V) which can be recrystallized from a suitable solvent e.g. ethyl ether.

The 2-phenoxyalkanoic acid (I) starting materials employed in the above reactions may be prepared by procedures known in the art, for example, the process described by Galimberti, P. and Defranceschi, A. in Gazz. Chim. ltal, 77, 431 (1947) as exemplified in hereinafter Example I. The other reactants e.g. the haloalkyl alkylethers (ll) and N-hydroxy succinimide or phthalimide (lV) employed in the above process are commercially available and/or may be prepared by well known chemical procedures. In the above reaction, by the term reaction-inert organic solvent is meant any organic solvent that will dissolve the reactants and not interfere with their interaction. Many such solvents will readily suggest themselves to those skilled in the art, e.g. ethyl acetate, chloroform, acetonitrile, dioxan and the like.

The new and novel Z-phenoxyalkanoic acid esters (Ill) and (V) of the present invention possess valuable pharmacological activity. In particular, these compounds in standard pharmacological procedures demonstrate an ability to reduce serum cholesterol and are useful as anticholesterol agents.

In the pharmacological evaluation of the cholesterol lowering properties of the compounds of this invention the in vivo effects of the compounds are tested as follows:

Male weanling rats are fed a hypercholesterolemic diet for three weeks. Serum cholesterol is determined on 0.01 ml of serum separated from tail blood collected in a capillary tube. Groups of rats with equal average serum cholesterol are given the test compound orally once a day by syringe for three days. Serum cholesterol is determined in the morning of the fourth day. Anticholesterol activity is demonstrated by a lowering of the serum cholesterol.

The Z-phenoxyalkanoic acid alkoxyalkyl esters (III),

the Z-phenoxyalkanoic acid succinimido esters (V) and 'the 2-phenoxyalkanoic acid phthalimido esters (V) of to remove excess iron and iron oxides. The ethanol water solution was stripped to remove the ethanol and the liquid product was separated from the aqueous phase, diluted with methylene chloride, dried and the formulated into herbicidal compositions and applied as herein illustrated, are:

R X 11. ltit It 11 n 11 R solvent stripped off. Obtained in this way was l97 g. of 5 C u 0 H (V I i a 7 J Y I I. the title compound, n,,' 1.6520. fair, 0 11 1:11; (:11: (:11: 1:11 o c2115 0 11;. C11, 11 11 11 1 25%? r: 11* 11 :1 11 1. EXAM L lV t-iliin o 11 11 11 11 11 1 (311: 611i c:111(; c113)= 0 11 11 11 11 11 1 (III; 011,1 l0 C2115 o 11 0113 011i 011, 11 1 11 11 2 8 i 8% 8E EFF i 1% li tr Preparation of 2(m O isopropylcarbamylphenyl)2 C213! 1 0 H Leah H 1 H 1 H 1 Cm CH3 methyl-1,3-d1th1olane c2115 s 11 CH1 CH1 c113 0111 0 Twelvhe anldzseverlil-tpntgsdgiamls (12.7 g1.) olf 2C(lrr1 EH1 in; in: S aminop eny) -met y-l, 1t 10 ane was ISSO ve in 1 1 Q 1 s 0 C 11 s 11 H H 11 11 1 CH. CH 100 ml. of acetone w1th 6.5 g. of trlethylamme and 7.4 15 t-im ig S I1 11 II 11 H 1 CH; CH: g. of isopropyl ehloroformate added portionwise with gig 5g 5% gn 5 i 1 s c 1 cooling. The mlxture was poured mto water, taken up L a S H H 1 1 H H 1n methylene chlor1de, dr1ed and the solvent stripped 11, s 11 141,111 H 11 11 1 e113 c113 under vacuum. There was obtained a yield of 15.2 g. of "03117 s H H H H 1 CH3 the title compound, an oil, n 1.6068.

EXAMPLE V HERBICIDAL SCREENING TESTS As previously mentioned, the herein-described compounds produced in the above-described manner are phytotoxic compounds which are useful and valuable in Preparatlon of y y controlling the growth of various plant species. Comphenyl)l.3-dlthlolane pounds of this invention are tested as herbicides in the Eleven and eight-tenths grams (11.8 g.) of 2(mf ll win manner, aminophenyl)l,S-dithiolane was dissolved in l00 ml. of 0 Pre-emei-gence h rbicide te t acetone with Of triethylamine and g. Of 3 0n the day preceding treatment seeds of even methyl chlorothiolformate was added portionwise with ferent weed species are planted in individual rows using cooling and stirring. The mixture was poured into water n S i r row ac oss th width of the flat, The and the solid product collected and dried. There was seeds used are hairy crabgrass (Digitaris sanguinalis obtained a yield of 15 g., m.p. l07lO9C. (1..) Scop.), yellow foxtail (Sezaria glauca (L.) Beauv.),

The following is a table of the compounds which are watergrass (Echinochlaa crusgalli (L.) Beauv.), Califorprepared according to the aforementioned procedures. nia red oat (Avena sativa (L.)), redroot pigweed Compound numbers have been assigned to them and (Amaranthus retroflexus (L.)), Indian mustard are used for identification throughout the balance of (Brassica juncea (L.) Coss.) and curly dock (Rumex the specification. crispus (L.)). Ample seeds are planted to give about 20 V i M'IABLE 1 A V A R2 R3 m SCC Ru c ai c so-- R1 L n l R4 R5 RX-(f-NH Compound l\l.1., C. number R X R R2 R3 R4 R5 11 R1, R1 or 21,,

0 CH; 11 H 11 11 0 11111-1118 o 0111 11 it 11 11 0 1.6068 s 011, 11 11 11 11 0 1.0171 s 011 11 11 11 11 0 70-711 s 11 11 11 11 11 1 151-153 s 11 11 11 11 11 0 107-10; 0 H 11 11 11 11 0 11104 1 Other examples of compounds falling within the generic formula presented herein, which are preparable to seedlings per row, after emergence, depending on the size of the plants. The flats are watered after plantby the aforedescribed procedures and which may be ing.

The spraying solution is prepared by dissolving 50 mg. of the test compound in 3 ml. of a solvent, such as acetone, water, alcohol or dimethylformamide, containing 1% Tween 20 (polyoxyethylene sorbitan monolaurate). When dimethylformamide is used, only 0.5 ml. or less is used to dissolve the compound. Another solvent is used to make the volume up to 3 ml. The following day after planting, each flat is sprayed at the rate of 20 pounds of the candidate compound per 143 gallons of solution per acre. An atomizer is used to spray the solution onto the soil surface. The flats are placed in a greenhouse at 7085F. and watered regularly by sprinkling. Two weeks after treatment, the degree of weed control is determined by comparing the amount of germination and growth of each weed in the treated flats with weeds in several untreated control flats. The rating system is as follows:

0 no significant injury (approximately 0-10 per cent control) slight injury (approximately -40 per cent control) 6 moderate injury (approximately 40-70 per cent control) 9 severe injury or death (approximately 70-100 per cent control) An activity index is used to represent the total activity on all seven weed species. The activity index is the sum of the numbers divided by 3, so that an activity index of 21 represents complete control of all seven weeds. The results of this test are reported in Table II.

Post-emergence herbicide test Seeds of five weed species, including hairy crabgrass, watergrass, California red oats, Indian mustard, and curly dock and one crop, pinto beans (Phaseolus vulgaris), are planted in flats as described above for pre-emergence screening. The flats are placed in the greenhouse at 72-85F. and watered daily with a sprinkler. About 10 to 14 days after planting, when the primary leaves of the bean plant are almost fully expanded and the first trifoliate leaves are just starting to form, the plants are sprayed. The spray is prepared by weighing out 50 mg. of the test compound, dissolving it is 5 ml. of acetone containing l percent Tween (poly- ,oxyethylene sorbitan monolaurate) and then adding 5 ml. of water. The solution is sprayed on the foliage using an atomizer. The spray concentration is 0.5 percent and the rate would be approximately 20 lb/acre if all of the spray were retained on the plant and the soil, but some spray is lost so it is estimated that the application rate is approximately 12.5 lb/acre.

Beans are used to detect defoliants and plant growth regulators. The beans are trimmed to two or three plants per flat by cutting off the excess weaker plants several days before treatment. The treated plants are placed back in the greenhouse and care is taken to avoid sprinkling the treated foliage with water for three days after treatment. Water is applied to the soil by means of a slow stream from a watering hose taking care not to wet the foliage.

Injury rates are recorded 14 days after treatment. The rating system is the same as described above for the pre-emergence test where (0), (3), (6), and (9) are used for the different rates of injury and control. The injury sumptoms are also recorded. The maximum activity index for complete control of all the species in the post-emergence screening test is 18. This index represents the sum of the rating numbers obtained with the six plant species used in the test divided by 3. The herbicide activity index is shown in Table I].

TABLE II HERBICIDAL ACTIVITY SCREENING RESULTS HERBICIDAL ACTIVITY INDEX COMPOUND Pre-emergence Post-emergence NUMBER (20 lb/A) (l2.5 lb/A) l 3 l 2 3 8 3 5 8 4 0 l 5 0 6 6 5 8 7 0 4 2l l00% control of all seven plant species tested preemergence. I8 70-100% control of all six plant species tested post-emergence.

The compounds of the present invention are used as pre-emergence or post-emergence herbicides and are applied in a variety of ways at various concentrations. In practice, the compounds are formulated with an inert carrier, utilizing methods well-known to those skilled in the art, thereby making them suitable for application as dusts, sprays, or drenches and the like, in the form and manner required. The mixtures can be dispersed in water with the aid of a wetting agent or they can be employed in organic liquid compositions, oil and water, water in oil emulsions, with or without the addition of wetting, dispersing or emulsifying agents. An herbicidally effective amount depends upon the nature of the seeds or plants to be controlled and the rate of application varies from 1 to approximately 50 pounds per acre.

The phytotoxic compositions of this invention employing an herbicidally effective amount of the compound described herein are applied to the plants in the conventional manner. Thus, the dust and liquid compositions can be applied to the plant by the use of powerdusters, boom and hand sprayers and spray-dusters. The compositions can also be applied from airplanes as a dust or a spray because they are effective in very low dosagesln order to modify or control growth of germinating seeds or emerging seedlings, as a typical example, the dust and liquid compositions are applied to the soil according to conventional methods and are distributed in the soil to a depth of at least k inchbelow the soil surface. It is not necessary that the phytotoxic compositions be admixed with the soil particles and these compositions can be applied merely by spraying or sprinkling the surface of the soil. The phytotoxic compositions of this invention can also be applied by addition to irrigation water supplied to the field to be treated. This method of application permits the penetration of the compositions into the soil as the water is absorbed therein. Dust compositions, granular compositions or liquid formulations applied to the surface of the soil can be distributed below the surface of the soil by conventional means such as discing, dragging or mixing operations.

The phytotoxic compositions of this invention can also contain other additaments, for example, fertilizers, pesticides and the like, used as adjuvant or in combination with any of the above-described adjuvants. Other phytotoxic compounds useful in combination with the above-described compounds include, for example, 2,4-dichlorophenoxyacetic acids, 2,4,5-trichlorophenoxyacetic acid, 2-methyl-4-chlorophenoxyacetic acid and the salts, esters and amides thereof; triazine derivatives, such as 2,4-bis(3-methoxypropylamino)-6- methyl-thio-S-triazine; 2-chloro-4-ethylamino-6-isopropylamino-S-triazine, and 2-ethylamino-4- isopropylamino--methylmercapto-S-triazine, urea derivatives, such as 3-(3,4-dichlorophenyl)-l,l-dimethyl urea and 3-(p-chlorophenyl-l,l-dimethyl urea and acetamides such as N,N-diallyl-a-chloroacetamide, N- (a-chloroacetyl)hexamethylene imine, and N,N-diethyl-a-bromacetamide, and the like; benzoic acids such as 3-amino-2,5-dichlorobenzoic; and thiocarbamates, such as S-propyl dipropylthiocarbamate; S-ethyldipropylthiocarbamate, S-ethylcyclohexyl-ethylthiocarbamate, S-ethyl hexahydro-lH-azepine-l-carbothioate and the like. Fertilizers useful in combination with the active ingredients include, for example, ammonium nitrate, urea and superphosphate. Other useful additaments include materials in which plant organisms take root and grow, such as compost, manure, humus, sand and the like.

The concentration of a compound of the present invention, constituting an effective amount in the best mode of administration in the utility disclosed, is readily determinable by those skilled in the art.

Various changes and modifications are possible without departing from the spirit and scope of the invention described herein and will be apparent to those skilled in the art to which it pertains. lt is accordingly intended that the present invention shall only'be limited by the scope of the claims.

What is claimed is:

l. A compound having the formula 8 in which R is lower alkyl; R,, R R;,, R.,, R R and R each are independently selected from the group consisting of hydrogen and lower alkyl; X is selected from the group consisting of oxygen and sulfur; and n is 0 or 1.

2. A compound according to claim 1 in which R is lower alkyl, X is oxygen, R, is lower alkyl and R R,,, R, and R are each independently hydrogen and n is 0.

3. A compound according to claim 2 in whichR is methyl and R, is methyl.

7 4. A compound according to claim 2 in which R is isopropyl and R, is methyl.

5. A compound according to claim 1 in which R is lower alkyl, X is sulfur, R, is lower alkyl and R R R, and R are each independently hydrogen and n is 0.

6. A compound according to claim 5 in which R is i 5 methyl and R, is methyl.

7. A compound according to claim 5 in which R is nbutyl and R, is methyl.

8. A compound according to claim 1 in which R is lower alkyl, X is sulfur, R,, R R R, and R are each independently hydrogen, n is 1 and R, and R are each hydrogen.

9. A compound according to claim 8 in which R is methyl.

10. A compound according to claim 1 in which R is lower alkyl, X is sulfur, R,, R R R, and R are each independently hydrogen and n is 0.

11. A compound according to claim 10 in which R is methyl.

12. A compound according to claim 1 in which R is lower alkyl, X is oxygen, R,, R R R, and R are each independently hydrogen, and n is 0.

13. A compound according to claim 12 in which R is isopropyl.

' Patent No. 3, 759, 95

UNITED STATES PATENT OFFICE CERTIFICATE "0F CORRECTION D d September 1 3, 1973 Inventor(s) Eugene G. Teach It is certified that error appears in the above-identified patent and that said Letters Patent are 'hereby corrected as shown below:

Cancel columns 1 and .2 of the printed patent and substitute the attached columns 1 and 2.

Signed and scaled this 30th day of April 197i (SEAL) Attest:

EDX-JARD M FLETCHER, JR. C MARSHALL DANN Commissionerof Patents Attesting (Lficer USCOMM-DC 603764 159 R U.5. GOVERNMENT PRINTING OFFICE: was 0-366-334,

F ORM PO-IOSO (10-69) CARBANILATE DITHI'OLANES AND DITHIANES This invention relates to certain novel substituted carbanilate dithiolanes and dithianes which are useful as herbicides. The compounds of the present invention are new compositions of matter and correspond to the formula embodiments are intended for the various substituents: Lower alkyl preferably includes, unless otherwise provided for, those members which contain from 1 to 6 carbon atoms, inclusive, in both straight chain and branched chain configurations, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, teitiary-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, and the like.

The compounds of this invention have been found to be active herbicides of a general type. That is, certain members of the class have been found to be herbicidally effective against a wide range of plant I species. A method of controlling undesirable vegetation of the present invention comprises applying an herbicidally effective amount of the above-described compounds to the area or plant locus where control like. By plants it is meant germinant seeds, emerging seedlings. and established vegetation. including the roots and above-ground portions.

The compounds of the present invention are prepared by several different methods. depending upon the nature of the starting materials and products desired. Synthesis of the starting materials can be found in several references in the literature. The following method is illustrative: Meta'nitrobenzaldehyde' (wherein R supra, is hydrogen), or 0 I meta-nitroacetophenone or higher phenones (where-, in R supra. is lower alkyl). are reacted with a suitable dithiol, either a 1,2 or 1.3-dithiol to give the desired cyclic mercaptalfThe corresponding cyclic mercaptal is reduced by conventional methods to give the corresponding meta-amino compound. The meta-amino compound is reacted with an appropriate acyl halide to obtain the desired substituted anilide, dithiolane or dithiane.

Particularly more illustrative of the above generally When the addition was complete and the mixture 5 EXAMPLE 1 Preparation of Intermediates 2(m-nitrophenyl) l ,3-dithiane otrenunaieaaaa sixtenths rass" (160.6 g.) of

m-nitro benzaldehyde, 72.4 g. of 1,3-propanedithiol and 1 g. of p-toluene sulfonic acidwere combined in 200 ml. of benzene and heated to reflux under a modified Dean-Stark apparatus. The mixture was heated until no more water came off (approximately 12 ml) and then cooled and the product crystallized.

There was obtained a yield of 149 g. of the title compound, M.P. l12-l 14C.

2(m-aminophenyl)1,3-dithiane One hundred grams g.) of iron powder was stirred with 250 ml. of ethanol and 200 ml. of water. 7 ml. of concentrated hydrochloric acid was added, and the mixture heated to reflux. One hundred and forty-one grams (141 g.) of 2(m-nitrophenyl)l,3- dithiane was added portionwise to maintain reflux. When addition was complete and the mixture had cooled about 10 below reflux, 7 g. of 50% sodium hydrate was added, the mixture filtered through a dicalite pad to remove e xcess iron and iron oxide and the ethanol solution was removed under vacuum. There was obtained 112.8 g. of the title compound, MP. 139-142c.

EXAMPLE II Preparation of 2(m-S-methylthiocarbamylphenyl) l ,3- 4 dithiane Twelve and seven-tentlfi grams (12.7 g.) of 2(mamino phenyl)l,3-dithiane was dissolved in 100 ml. of acetone with 6.5 g. of triethylamine and 6.7 g. of methyl chlorothiol formate was added portionwise with cooling and stirring. The mixture was poured into water and the solid product collected by filtration and dried. There was obtained a yield of 13.8 g. of the title compound, M129 5 1 C. The product was triturated with diethyl ether to give a product,

EXAMPLE in 5' i Preparation of Intermediates 2(m-nitrophenyl)2-methyll ,3-dithiolane One hundred and seventy-five grams g.) of m-nitro acetophenone, 100 g. of ethane dithiol and 1 g. of p-toluene sulfonic acid were combined in 300 2(m-aminophenyl)2-methyl-l ,3-dithiolane One hundred and eighty grams g.) of iron powder, 375 ml. of ethyl alcohol and 300 ml. of water and l2 ml. of concentrated hydrochloride acid were stirred together and heated'toreflux. Two hurTdred and fifty-two grams (252 g.) of 2(m-nitrophenyl)2-methyl- 1,3-dithiolane was added dropwise to maintain reflux.

cooled about 10.- 12 g. of 50% sodium hydroxide was added and the. mixture filtered through a dicalite pad 

2. A compound according to claim 1 in which R is lower alkyl, X is oxygen, R1 is lower alkyl and R2, R3, R4 and R5 are each independently hydrogen and n is
 0. 3. A compound according to claim 2 in which R is methyl and R1 is methyl.
 4. A compound according to claim 2 in which R is isopropyl and R1 is methyl.
 5. A compound according to claim 1 in which R is lower alkyl, X is sulfur, R1 is lower alkyl and R2, R3, R4 and R5 are each independently hydrogen and n is
 0. 6. A compound according to claim 5 in which R is methyl and R1 is methyl.
 7. A compound according to claim 5 in which R is n-butyl and R1 is methyl.
 8. A compound according to claim 1 in which R iS lower alkyl, X is sulfur, R1, R2, R3, R4 and R5 are each independently hydrogen, n is 1 and R6 and R7 are each hydrogen.
 9. A compound according to claim 8 in which R is methyl.
 10. A compound according to claim 1 in which R is lower alkyl, X is sulfur, R1, R2, R3, R4 and R5 are each independently hydrogen and n is
 0. 11. A compound according to claim 10 in which R is methyl.
 12. A compound according to claim 1 in which R is lower alkyl, X is oxygen, R1, R2, R3, R4 and R5 are each independently hydrogen, and n is
 0. 13. A compound according to claim 12 in which R is isopropyl. 